Online Seminar: From Ion Channel Gating Pore Currents to International Genomic Medicine Initiatives in Neuromuscular Diseases

MDUK OXFORD NEUROMUSCULAR CENTRE SEMINAR SERIES

REGISTRATION

This seminar is intended for the personnel and students at the University of Oxford and the Oxford University Hospitals Foundation Trust.

Online Seminar - please follow the link here to register.

ABSTRACT

Single gene neurological channelopthies are increasingly recognised and often present with paroxysmal neurological dysfunction. The muscle channelopathies are amongst the best characterised channelopathies at a clinical, pathophysiological and molecular genetic level. They include a wide range of phenotypes including, fetal hypokinesia, neonatal hypotonia, neonatal stridor, congenital and adult onset myopathy, periodic paralyses (PPs) and inherited myotonias. A large number of mutations in voltage gated skeletal muscle sodium, calcium, potassium and chloride channel genes link to these disorders and molecular mechanisms are being elucidated, with therapy implications.

PPs are well characterised at genetic, pathophysiological and clinical levels and include hypokalemic paralysis, hyperkalemic paralysis, and Andersen-Tawil syndrome and examples will be presented. Common features include autosomal dominant inheritance, onset typically in the first or second decades and episodic attacks of flaccid weakness often triggered by diet or rest after exercise. A progressive myopathy often develops. Diagnosis is based on clinical, electrophysiological and genetic findings. The treatment approach includes both management of acute attacks and prevention of attacks including with modification of potassium levels, diuretics, and carbonic anhydrase inhibitors.

Recent work has led to increased understanding of the molecular pathophysiology of these disorders. For example, sodium channel dysfunction includes defects in fast inactivation (a gain of function) which cause hyperPP and different myotonias. In addition, we identified a new set of loss of sodium channel function mutations presenting with neonatal hypotonia and congenital myopathy. A common theme of S4 voltage sensor loss of charge mutations in either a sodium or a calcium channel, which predict a gating pore current, has been linked to hypokalaemic periodic paralysis.

I will present example clinical phenotypes and outline genetics and underlying pathophysiological mechanisms-the understanding of which are informing therapy development.

SPEAKER

Michael Hanna is Professor of Clinical Neurology and Director at the UCL Institute of Neurology, Queen Square. He is a Consultant Neurologist at the National Hospital for Neurology. In 2001 he established and leads the NHS England highly specialised clinical and diagnostic service for muscle channelopathies; working with a highly skilled multidisciplinary team of clinicians, geneticists and channel biophysicists enabling accurate diagnosis and treatment for patients nationally. He established and led the MRC Centre for Neuromuscular diseases from 2008-2020, which developed a successful nationally coordinated experimental medicine, research training and genetic research platform. In 2019 he led a bid for £5m to establish the MRC International Centre for Genomic Medicine in Neuromuscular Diseases spanning 14 centres in five counties. He has published over 500 peer-reviewed articles; and is a Fellow and Council member of the Academy of Medical Sciences.

Queen Square Centre for Neuromuscular Diseases Website

Professor Hanna's Profile on UCL Website

About the queen square institute of neurology

The UCL Queen Square Ins titute of Neurology (IoN) has a world-class reputation for neuroscience.  The mission is to translate neuroscience discovery research into treatments for patients with neurological diseases.  A number of important research centres are based at the Institute, including the MRC International Centre for Genomic Medicine in Neuromuscular Diseases and the Wellcome Centre for human Neuroimaging.

The Institute has eight academic Departments, which encompass clinical and basic research within each theme. In parallel, there are six cross cutting Divisions representing clinical professional affiliations.

The current Director is Professor Michael Hanna FRCP MD FMedSci

The Institute has a significant postgraduate teaching and training portfolio, with nearly 500 graduate students at Queen Square. The Institute employs just over 750 staff, and hosts just under 300 honorary & visiting staff, spread over a complex and large estate comprising of over 15 buildings and it is expanding its preclinical research facilities into a major new £281m translational neuroscience building to be completed in 2024. The Institute currently holds 627 active research projects, totalling £304 million. It is host to the HQ of the £250m MRC UK Dementia Research Institute. The IoN annual turnover is £85 million. There are 130 Principal Investigators at IoN, including: 114 professors/ professorial research associates and 25 emeritus professors; 11 Fellows of the Royal Society; 29 Fellows of the Academy of Medical Sciences; 1 Nobel Prize winner.

about the mrc international centre for genomic medicine in neuromuscular diseases

The MRC International Centre for Genomic Medicine in Neuromuscular Diseases (ICGNMD) is a £5m investment with £3.6m MRC and £1.4m from host Universities UCL, Newcastle and Cambridge. Genomic medicine has transformed diagnostics and enabled therapy development in Neuromuscular Diseases in developed countries. However, an estimated 17m NMD patients in less developed countries are yet to access the benefits of genomic medicine. ICGNMD aims to develop a genomic medicine partnership programme in neuromuscular diseases between UK centres and Lower and Middle Income Countries and has partnered with 14 centres across five LMICs. Its broad aims include

1. Building an international, “trial-ready”, deeply-phenotyped & fully genotyped cohort of patients with inherited neuromuscular diseases (NMDs)

2. Define the genetic architecture of NMD in different populations and link this to trials and improved care pathways

3. Growing capacity in neuromuscular disease clinical academics who are trained in genomic medicine with an initial international cohort of 14 clinical academic fellows

4. Developing NMD research and capacity-building partnerships across 14 Centres in Brazil, India, South Africa, Turkey, the UK and Zambia.

Our ultimate aim is to improve health outcomes for people with NMDs, affecting ~17million people globally.